Transmissible spongiform encephalopathies (TSE) are a group of rare neurodegenerative diseases which include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and chronic wasting disease (CWD) in mule deer and elk. TSE infectivity can cross species barriers. The fact that BSE has infected humans in Great Britain underscores the importance of understanding TSE pathogenesis and developing effective anti-TSE therapeutics. The precise nature of the infectious agent of the TSE diseases is unknown. Susceptibility to infection can be influenced by amino acid homology between a normal host protein (PrP-sen) and the abnormal proteinase K-resistant form of this protein, PrP-res. Formation of PrP-res is closely associated with infectivity and PrP-res has been hypothesized to be the infectious agent in the TSE diseases. An understanding of how this protein is made is critical for our understanding of TSE pathogenesis and for devising therapeutic strategies to prevent its synthesis. My studies address many different aspects of the TSE diseases at both the molecular and pathogenic level. In particular, my laboratory focuses on: 1) determing how different PrP-sen secondary structures are involved in PrP-res formation, 2) precisely defining the different cellular compartments where PrP-res formation occurs, 3) development of effective therapeutic TSE agents, 4) identifying the earliest events which occur during TSE infection, and 5) determining the molecular basis of TSE strains. At the molecular level, we have shown that the amino acids that influence species-specific PrP-res formation differ between species. We have also demonstrated that different secondary structures in PrP-sen influence PrP-res formation by altering PrP-sen processing and/or folding. Using a tissue culture system we have developed, we have begun to dissect TSE strain-specific differences in both PrP-res formation and susceptibility to infection. As a result of these studies, we have found that non-neuronal cell types can be susceptible to TSE infection. In terms of therapeutic approaches, we have found that the cyclic tetrapyrolle phthalocyanine tetrasulfonate can be used prophylactically to delay disease onset in a murine model of TSE disease.